Antitussive composition



United States Patent t ,0 ,74 ANTITUSSIVE COMP'OSITIDN Alberto Vecchiand Giulio Maiiii, Milan, Italy, assignors to Lepetit S.p.A., Milan,Italy No Drawing. Filed July 1, 1959, Ser. No. 824,183

6 Claims. (Cl. 167-'-55) ofN,N-dimethyl-Z-phenyLZ-benzoyloxymethylbutylamine O ll 7 O C CH3011301120 CHQN and its non-toxic mineral acid addition salts.

The compound of the invention, which for therapeutic purposes is bestused in the form of the hydrochloride, owing to its mechanism of action,is to be classified among the centrally acting antitussive agents, as ithas been shown by pharmacological tests. Moreover, it lacks any narcoticaction, thus proving in this respect superior to many natural orsynthetic drugs commonly employed in the management of coughing.

The search for central acting, non-narcotic antitussive substances hasbeen fairly intense in recent years, and has brought about the use ofsome therapeutic agents which are capable of increasing the threshold ofthe medullary cough center to afferent tussive impulses without theundesirable effects of narcotics. It has now been found thatN,N-dimethyl-Z-phenyl 2 benzoyloxymethylbutylamine displays anantitussive effect which is favorably comparable with that of codeineand narcotine, and is free from the well known side efiects of thesegenerally employed drugs.

The following table gives the average protecting dose, in mg./kg., ofthe compound of the invention against cough caused by the inhalation ofacrolein in the form of aerosol in guinea pigs, by stimulation of thelaryngeal nerve in cats and by inhalation of sulfuric acid in dogs. Thedata are compared with those obtained with codeine and narcotine undersimilar conditions.

The acute toxicity of the compound of the invention is also veryfavorable, as is shown by the following comparative table.

3,673,741 Patented Jan. 1 1953 For therapeutical purposes,N,N-dimethl-2-phenyl-2- benzoyloxymethylbutylamine and its mineral acidsalts may be used as such as associated with a carrier, which may be asolid material, a sterile parenteral liquid or a syrup. When the oraladministration is selected as conimonly used for this type of drugs thetherapeutic administration may be providedin the form of powders,capsules, tablets or other solid dosage forms. For parenteral use,liquid diluents may be employed, such as sterile distilled water, inwhich the mineral acid salts are freely soluble. Although clinicallyappreciable effects are observed with doses as low as l-10 mg, the unitdosage is usually somewhat higher, and may safely reach 500 mg. and morein stubborn cases. Preferably the doses are maintained under 50 mg,owing to the great efiiectiveness of the compound. For preparing theactual therapeutic composition, the selected dose of the drug may bedirectly filled into capsules, either alone 01' associated with solidinert diluents and/or other active ingradients. Tablets may be preparedby associating the drug with the commonly used tableting materials, suchas lactose, talc, cornstarch, stearic acid, magnesium stearate or thelike. Ampoules are prepared by dissolving the drug, in the form of itsmineral acid salts, in sterile distilled water. The composition may alsoadvantageously take the form of a syrup, whereby the drug is dissolvedin the common syrup in a concentration calculated so as to administerthe proper dose, with or without the addition of suspending and/orflavoring agents and/or other drugs.

N,N-dimethyl-Z phenyl 2 benzoyloxymethylbutylamine may be preparedstarting from a-carbethoxy-aphenylbutyric acid through the correspondingchloride, which in turn is converted to the dimethylamide by reactionwith dimethylamine in an inert anhydrous organic solvent. Byhydrogenation with lithium aluminum hydride N,N dimethyl 2phenyl-2-hydroxymethylbutylamine is obtained which on treatment withbenzoyl chloride in anhydrous pyridine gives the compound of theinvention.

The following examples are illustrative of the invention.

Example 1 A mixture of 32 g. u-carbethoxy-a-phenylbutyric acid and 25ml. thionyl chloride is refluxed for 2 hours. The excess thionylchloride is removed in vacuo and the residue is distilled collecting atl04-l06 C. under 1 mm. Hg. Yield: 30 g. (87%)ot-carbethox-a-phenylbutyryl chloride. M.P. 35-40" C.

The above acyl chloride is mixed with ml. of a 17.5% solution ofdimethylamine in benzene. After 15 minutes the solution is treated withwater, made acidic with hydrochloric acid and extracted with ethylether.

The organic layer is separated and evaporated to dryness. The residualcrude product is recrystallized from ligroin. Yield: 28 g. (90%)N,N-dimethyl-u-pheny1-acarbethoxymethylbutyramide.

Into a mixture of 17.4 g. lithium aluminium hydride in 150 ml. anhydrousethyl ether a solution of g. ZN,N-dimethyl-a-phenyl-a-carbethoxymethylbutyramide in 90 ml. anhydrous ethylether is gradually dropped without exceeding 25-27 C. The mixture isthen refluxed for 1.5 hours and poured cautiously after cooling into 2volumes of cold water. The mixture is extracted with ethyl ether and theorganic layer is evaporated to dryness in vacuo. The residual oil (9 g.,yield 76%) is N,N- dimethyl-Z-phenyl-Z-hydroxymethylbutylamine. Thehydrochloride melts at 116118 C.

To a susepnsion of 7.9 g. of the amine in 35 ml. anhydrous pyridine 8.5g. benzoyl chloride are gradually added in about 15 minutes below 15 C.After stirring for 1 hour at room temperature the mixture is poured into2 volumes of water. The pH is adjusted to 8.5 and the mixture isextracted with ethyl ether. The solvent and the traces of pyridine arecarefully removed, then the residual oil is dissolved in ethyl ether anddiluted with an ethyl ether solution of hydrogen chloride. Theprecipitated crystals are collected and recrystallised from ethylacetate. Yield: 12 g. (90%) of N,N-dimethyl-2-phenyl-Z-benzoyloxymethylbutylamine, M.P. 17l173 C.

The free base may be obtained in a pure grade by dissolving thehydrochloride in water, making the solution alkaline, extracting withethyl ether and evaporating the extract to dryness.

Example 2 Three grams ofN,N-dimethy1-2-phenyl-2-benzoyloxymethylbutylamine are filled into onehundred capsules and are ready for therapeutic use.

The mixture is tabletted to one hundred tablets ready for therapeuticuse.

Phosphoric acid 0.09 Syrup of lemon, to m1.

It contains about 0.05 g. of the drug in 5 ml.

We claim:

1. An antitussive composition in dosage unit form, which comprises from0.01 to 0.5 gram of N,N-dimethyl- 2-phenyl-2-benz0yloxymethylbutylaminetogether with a diluent.

2. An antitussive composition in dosage unit form, which comprises from0.01 to 0.5 gram of ILN-dimethyl- 2-phenyl-2-benzoyloxymethylbutylamineper dosage unit and a solid pharmaceutical carrier.

3. An antitussive composition in dosage unit form, which comprises from0.01 to 0.5 gram of N,N-dimethyl- 2-phenyl 2 benzoyloxymethylbutylaminehydrochloride per dosage unit and a liquid diluent.

4. An antitussive composition as in claim 3, wherein the liquid diluentis sterile distilled water.

5. An antitussive composition in syrup form, which comprises from 0.1 to1.0 percent of N,N-dimethyl-2- phenyl-Z-benzoyloxymethylbutylaminehydrochloride, to gether with a syrupy pharmaceutical carrier.

6. An antitussive composition containing in a dosage unit form from 0.01to 0.5 gram of a member of the group consisting ofN,N-dimethyl-2-phenyl2-benzoyloxymethylbutylamine and its non-toxicmineral acid salts, together with a diluent.

References Cited in the file of this patent UNITED STATES PATENTS 81,446Whitlow Aug. 25, 1868 1,794,292 H0110 Feb. 24, 1931 2,421,129 ReasenbergMay 27, 1947 2,486,375 Cope Nov. 1, 1949 FOREIGN PATENTS 17,085 GreatBritain 1914

1. AN ANTITUSSIVE COMPOSITION IN DOSAGE UNIT FORM, WHICH COMPRISES FROM0.01 TO 0.5 GRAM OF N,N-DIMETHYL2.PHENYL-2-BENZOYLOXYMETHYLBUTYLAMINETOGETHER WITH A DILUENT.